Long-Term Enzyme Replacement Therapy and Renal Outcomes in Fabry Disease: A Systematic Review and Meta-Analysis

Background: Fabry disease is a rare X-linked lysosomal storage disorder associated with progressive renal, cardiac, and neurological complications. Enzyme replacement therapy (ERT) has been the standard treatment for more than two decades, but its long-term impact on renal outcomes remains debated. Methods: We conducted a systematic review and meta-analysis of studies reporting renal outcomes in Fabry patients under long-term follow-up, including both ERT-treated and untreated cohorts. Electronic databases were searched up to October 2023. Data were extracted on estimated glomerular filtration rate (eGFR) slope, proteinuria, and clinical events. Random-effects models were used to calculate pooled effect sizes, and subgroup analyses were performed by treatment status and baseline risk factors. Results: Sixteen studies involving 2191 patients were included. Pooled analyses demonstrated a significant decline in eGFR over time across Fabry cohorts. Crucially, baseline proteinuria was identified as a significant prognostic factor; male patients with baseline UPCR > 0.5 g/g experienced a significantly faster decline in eGFR compared to those with UPCR < 0.5 g/g (p = 0.011). While direct comparisons between ERT and non-ERT groups did not consistently reach statistical significance, trends suggested a slower decline in ERT-treated patients, particularly in those with preserved renal function and lower proteinuria. Patients with baseline eGFR < 60 mL/min/1.73 m² had a significantly higher risk of clinical events compared with those with preserved renal function. Conclusions: Fabry patients experience progressive renal decline despite available therapies. Although direct comparisons between ERT and non-ERT groups did not consistently reach statistical significance, our quantitative analysis highlighted baseline proteinuria as a major determinant of renal trajectory. Patients with baseline UPCR > 0.5 g/g exhibited a significantly faster decline in eGFR, emphasizing the importance of early diagnosis and intervention before significant glomerular damage occurs. The limitations of the analysis include the small number of studies, heterogeneity in renal function definitions, exclusion of advanced kidney disease, and methodological constraints related to effect size reporting and risk-of-bias assessment.